Reconsidering the Polypill for Management of Cardiovascular Risk Factors in Underserved Patients.

PURPOSE OF REVIEW: The recent publication of "Polypill for Cardiovascular Disease Prevention in an Underserved Population" study prompts a thoughtful review of known care disparities in cardiovascular disease management in underserved patients. A polypill approach as a population health solution to this complex problem should also be reviewed. RECENT FINDINGS: Muñoz and colleagues open-label, randomized controlled trial of polypill vs. usual care was undertaken in minority patients at a federally qualified health center. The polypill, containing atorvastatin, amlodipine, losartan, and hydrochlorothiazide resulted in statistically significant improvements in systolic blood pressure and low-density lipoprotein levels (p = 0.003 and p < 0.001, respectively). The significant results of this study demonstrate the ability of a polypill approach to safely lower blood pressure, lipids, and thus estimated 10-year risk of CVD and are consistent with findings observed in previous literature. Uniquely, findings in a largely non-Hispanic Black patient population, offer an opportunity to examine this approach to combat important disparities in care in an underserved U.S. community. Further outcomes-based studies are warranted to explore the validity of these results and long-term safety of polypill treatment and are likely necessary prior to FDA approval and availability of a polypill product.

A comparison of anticoagulation, antiplatelet, and placebo treatment for patients with heart failure reduced ejection fraction in sinus rhythm: a systematic review and meta-analysis.

Previous meta-analyses have not recommended routine warfarin use in heart failure (HF) patients but included limited data on contemporary anticoagulants and practices. We conducted an updated meta-analysis in light of newer literature evaluating rivaroxaban in this patient population. The aim of this meta-analysis was to assess if anticoagulation is associated with a decrease in all-cause mortality, myocardial infarction (MI), stroke, and hospitalization for HF exacerbation without an increased risk of major bleeding. A systematic search was conducted for randomized controlled trials to evaluate the use of antithrombotic therapy in patients with HF in sinus rhythm. Outcomes evaluated included all-cause mortality (ACM), non-fatal stroke, MI, hospitalization for HF exacerbation, and major bleeding. Five trials met criteria with a total of 9390 patients included. Four of the five trials evaluated warfarin use and one trial evaluated rivaroxaban. When anticoagulation was compared to control (antiplatelet and placebo groups), a significant reduction in ischemic stroke was found (OR 0.57; 95% CI, 0.42 to 0.78; P = 0.0005, I2 = 6.9%) and no significant difference was found in the risk of ACM, MI, or HF hospitalization. A significant increase in major bleeding was observed in the anticoagulation group when compared to the control group (OR 2.00; 95% CI, 1.45 to 2.75; P = < 0.0001, I2 = 25.79%). Anticoagulation in HF patients in normal sinus rhythm does not appear to reduce mortality rate, prevent MI, or decrease HF hospitalizations. Use reduces risk of ischemic stroke but is counterbalanced with an increase in major bleeding.

Reduced dose thrombolysis with ultrasound-facilitated catheter-directed administration for acute pulmonary embolism reduces length of stay.

The optimal dose and duration of tissue plasminogen activator (tPA) administered with ultrasound-facilitated catheter-directed thrombolysis (USCDT) to patients with acute PE remains to be determined. Our institution recently adopted a shorter duration (4 h) of USCDT and lower dosing strategy (tPA 1 mg/h) based on data from the OPTALYSE PE Trial. The purpose was to evaluate the implementation at our institution of shorter duration (4 h) of USCDT and lower dosing strategy (tPA 1 mg/h) as outlined by OPTALYSE PE Trial. This was a retrospective, single-center, observational study included patients from 01/01/2017 to 12/31/2018 in a large, academic medical center. Group 1 represented patients who underwent USCDT prior to 01/18/18. Group 2 represented patients who underwent USCDT after 01/18/18 and received 4 h of USCDT and tPA 1 mg/h/catheter. The primary outcome was intensive care unit (ICU) length of stay (LOS). Secondary outcomes were the proportion of patients experiencing a composite of major adverse events (death, recurrent PE, major bleeding, or stroke), change in right ventricle size/function and pulmonary artery pressures, need for mechanical respiratory or hemodynamic support, hospital LOS and drug cost. A total of 31 patients were included in the study: twenty patients in Group 1 and eleven patients in Group 2. Median ICU LOS was 3.5 days in Group 1 and 1 day in Group 2. Group 2 had reduced MACE, requirement for mechanical respiratory or hemodynamic support, hospital LOS, drug costs and adverse events. Implementation of a shorter duration of USCDT and lower dosing strategy for tPA in patients with acute PE may be one strategy to reduce the total ICU LOS and costs associated with care.

Cardiovascular Risk Reduction by Pharmacists at the Workplace.

PURPOSE OF REVIEW: The burden of cardiovascular disease (CVD) in the USA remains unacceptably high. The associated morbidity and mortality of CVD has important implications on our healthcare system and society. With much of CVD considered preventable an increase emphasis on primary prevention is important. To review the evidence for pharmacists providing CVD primary prevention, particularly as a part of employer-based programs. RECENT FINDINGS: A recent study evaluated the impact of a pharmacist-led 12-month preventative health program in 178 at-risk employees at University of British Columbia (UBC). Cardiovascular Assessment and Medication Management by Pharmacists at UBC (CAMMPUS) resulted in improved Framingham risk scores (FRS) from 11.7 to 10.7 (p = 0.0017), improvement in quality of life (p = 0.023), and medication adherence (p = 0.019). Findings are consistent with improvements observed in other pharmacist-led intervention trials but offer the unique perspective as an employer-based intervention. Pharmacists-led interventions prevent CVD through improvement in health markers and medication adherence. The ability of pharmacists to provide these as part of an employer-sponsored benefit might be favorable as other billing models for pharmacist can be challenging to be justified in a fee-for-service payment structure; further, there is incentive for employers to lower healthcare cost and improve productivity. Future studies defining the impact of pharmacists in this and other settings may have important public health implications.

The effect of rosuvastatin on thromboinflammation in the setting of acute coronary syndrome.

In patients with acute coronary syndromes (ACS), early therapy with high-dose statins may reduce short-term adverse clinical outcomes. The mechanisms responsible are not known but could involve anti-inflammatory or anti-thrombotic effects. Compelling evidence from experimental models and clinical studies suggests that the interplay between inflammatory and thrombotic systems, typified by platelet-monocyte and platelet-neutrophil interactions, might be a key regulator of ischemic vascular events. The study sought to determine if early, high-dose administration of the HMG-CoA reductase inhibitor rosuvastatin in the setting of ACS exerts beneficial vascular effects by reducing, and inhibiting biomarkers of thromboinflammation, such as platelet-monocyte and platelet-neutrophil interactions, and biomarkers of myocardial necrosis. A total of 54 patients presenting with ACS within 8 h of symptom onset were randomized to rosuvastatin 40 mg or placebo. Rosuvastatin significantly reduced interactions between platelets and circulating neutrophils (P = 0.015) and monocytes (P = 0.009) within 24 h. No significant effects were observed on platelet aggregation or plasma levels of PF4, sP-selectin, or sCD40L, whereas significant reductions of RANTES occurred over time in both treatment groups. Plasma levels of myeloperoxidase (MPO) declined more rapidly with rosuvastatin therapy than placebo. In a subset of patients with normal cardiac necrosis biomarkers at randomization, rosuvastatin therapy was associated with less myocardial damage as measured by troponin-I or CK-MB. Early administration of high-dose statin therapy in patients with ACS appears to improve biomarkers of inflammation within 8 h, which may translate into fewer ischemic events.

Increased mortality among patients taking digoxin--analysis from the AFFIRM study.

AIMS: Digoxin is frequently used for rate control of atrial fibrillation (AF). It has, however, been associated with increased mortality. It remains unclear whether digoxin itself is responsible for the increased mortality (toxic drug effect) or whether it is prescribed to sicker patients with inherently higher mortality due to comorbidities. The goal of our study was to determine the relationship between digoxin and mortality in patients with AF. METHODS AND RESULTS: The association between digoxin and mortality was assessed in patients enrolled in the AF Follow-Up Investigation of Rhythm Management (AFFIRM) trial using multivariate Cox proportional hazards models. Analyses were conducted in all patients and in subsets according to the presence or absence of heart failure (HF), as defined by a history of HF and/or an ejection fraction <40%. Digoxin was associated with an increase in all-cause mortality [estimated hazard ratio (EHR) 1.41, 95% confidence interval (CI) 1.19-1.67, P < 0.001], cardiovascular mortality (EHR 1.35, 95% CI 1.06-1.71, P = 0.016), and arrhythmic mortality (EHR 1.61, 95% CI 1.12-2.30, P = 0.009). The all-cause mortality was increased with digoxin in patients without or with HF (EHR 1.37, 95% CI 1.05-1.79, P = 0.019 and EHR 1.41, 95% CI 1.09-1.84, P = 0.010, respectively). There was no significant digoxin-gender interaction for all-cause (P = 0.70) or cardiovascular (P = 0.95) mortality. CONCLUSION: Digoxin was associated with a significant increase in all-cause mortality in patients with AF after correcting for clinical characteristics and comorbidities, regardless of gender or of the presence or absence of HF. These findings call into question the widespread use of digoxin in patients with AF.

An inter-institutional PharmD elective course and qualitative analysis exploring student engagement and collaboration.

BACKGROUND AND PURPOSE: There are limited reports in the literature of integrated inter-institutional doctor of pharmacy (PharmD) coursework where learners and faculty are connected using synchronous web conferencing. Furthermore, the impact of this learning environment on student engagement and collaboration has not been reported previously. EDUCATIONAL ACTIVITY AND SETTING: Faculty members from two separate schools of pharmacy collaborated to create the Current Concepts and Controversies in Cardiology (C4) elective, a two-credit hour elective course that was delivered via synchronous web conferencing. The course was designed to build upon students' pre-existing cardiovascular knowledgebase using case-based discussions, critical appraisal of clinical trials, and pro/con debates. Qualitative analysis using semi-structured interviews was performed to explore aspects of the course that promoted, or hindered, students' engagement and collaboration. FINDINGS: Seven students completed the semi-structured interviews following completion of the course. Themes identified that promoted student engagement and collaboration included, but were not limited to, observing professional relationships and interactions among faculty as well as faculty specifically calling on students by name or location. Three themes were found to be barriers to engagement and collaboration across institutions and included glitches in technology, the adversarial setup of the pro/con debates, and the inability to partake in impromptu discussion before and after class. SUMMARY: The C4 elective course was an integrated inter-institutional PharmD elective delivered using web conferencing. We highlight aspects of the course that promoted engagement and collaboration. The impact of inter-institutional PharmD education remains largely unexplored but may be an area of future interest and research.

The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema.

OBJECTIVE: To assess the safety of using angiotensin II receptor blockers (ARBs) in patients who develop angioedema with the use of angiotensin-converting enzyme inhibitors (ACEIs). DATA SOURCES: A literature search was performed using MEDLINE (1977-January 2011) and Cochrane Library, using the terms angiotensin receptor blocker, angiotensin-converting enzyme inhibitor, and angioedema. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: Only English-language publications were included. Randomized controlled trial data, observational studies (retrospective and prospective), and case reports on adults who received ACEI therapy and then an ARB as an alternative therapy were reviewed. DATA SYNTHESIS: Two randomized controlled trials and 1 meta-analysis evaluated ARB use in patients intolerant to ACEIs. Taken together, there is a conservative estimate of a 10% or less incidence of cross reactivity of angioedema in patients who receive an ARB after experiencing ACEI-associated angioedema. Angioedema related to ARBs is reported to be less severe and occurs earlier compared to angioedema that develops during ACEI therapy. CONCLUSIONS: ARBs may be an alternative for patients who develop angioedema while using an ACEI but should be reserved for patients with high therapeutic need for angiotensin inhibition. Treatment should be started with observation, patients should be educated on the signs of angioedema, and proper emergency management should be emphasized to patients and care providers.

Evaluation of a clinical scoring scale to direct early appropriate therapy in heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a serious adverse effect associated with heparin therapy. Current laboratory confirmation for immune mediated HIT often results in false positives and unnecessary treatment, exposing individuals to possible complications. As a result, clinical evaluation has been recommended in conjunction with laboratory testing. We hypothesize that utilization of a clinical scoring scale, the 4T's, will result in the initial appropriate therapy for suspected HIT. METHODS: This is a retrospective chart review of 108 patients who underwent ELISA testing for HIT at a university hospital. The 4T's scale was applied, stratifying individuals into low, intermediate, and high-risk categories. Each risk score was compared to the ELISA results to determine if the 4T's can predict the diagnosis of HIT and result in appropriate management. ELISA optical density scores as well as incidence of adverse events were also compared among risk categories. STUDY RESULTS: Individuals with low risk correlate with a negative ELISA compared to intermediate and high-risk individuals (p = 0.01 and p<0.01) and also were significantly more likely to predict institution of appropriate therapy (p<0.01). Median optical density scores were 0.184 (0.046-2.116), 0.226 (0.067-1.887), and 0.476 (0.096-1.309) for low, intermediate, and high 4T scores. Major adverse events include thrombosis and bleeding. CONCLUSIONS: Individuals with low risk were more likely to receive initial, appropriate therapy and were also significantly more likely to have a negative ELISA test result. Individuals with low risk determined by the 4T score therefore may have therapy and serologic testing for HIT withheld.

A Review of Hypertension Management in Black Male Patients.

Hypertension affects approximately 85 million Americans, or almost 1 in 3 adults. Black men have disproportionately higher rates of hypertension and are more likely to experience complications of hypertension, including stroke, myocardial infarction, and death. In addition, hypertensive black men are less likely to achieve optimal blood pressure (BP) than women and persons of other races. In light of this, we performed a literature search for articles published from January 1, 1966, to December 31, 2018, using terms including hypertension, blood pressure, black male, and African American male. Studies were selected for inclusion according to their relevance regarding hypertensive management in black men. Subsequent findings indicated that targeted identification (ie, barbershops), medication management, and close follow-up resulted in greater control of BP. Also, a reduction of systolic blood pressure greater than 20 mm Hg occurred with the use of pharmacists following algorithms specifically for the management of hypertension in black men. Continued emphasis to identify strategies to improve control of BP and outcomes in this population is needed.

COVID-19 pandemic: Challenges and solutions from the cardiology pharmacist's perspective.

The recent coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenges pharmacists worldwide. Alongside other specialized pharmacists, we re-evaluated daily processes and therapies used to treat COVID-19 patients within our institutions from a cardiovascular perspective and share what we have learned. To develop a collaborative approach for cardiology issues and concerns in the care of confirmed or suspected COVID-19 patients by drawing on the experiences of cardiology pharmacists across the country. On March 26, 2020, a conference call was convened composed of 24 cardiology residency-trained pharmacists (23 actively practicing in cardiology and 1 in critical care) from 16 institutions across the United States to discuss cardiology issues each have encountered with COVID-19 patients. Discussion centered around providing optimal pharmaceutical care while limiting staff exposure. The collaborative of pharmacists found for the ST-elevation myocardial infarction patient, many institutions were diverting COVID-19 rule-out patients to their Emergency Department (ED). Thrombolytics are an alternative to percutaneous coronary intervention (PCI) allowing for timely treatment of patients and decreased staff exposure. An emergency response grab and go kit includes initial drugs and airway equipment so the patient can be treated and the cart can be left outside the room. Cardiology pharmacists have developed policies and procedures to address monitoring of QT prolonging medications, the use of inhaled prostacyclins, and national drug shortages. Technology has allowed us to practice social distancing, while staying in close contact with our teams, patients, and colleagues and continuing to teach. Residents are engaged in unique decision-making processes with their preceptors and assist as pharmacist extenders. Cardiology pharmacists are in a unique position to work with other pharmacists and health care professionals to implement safe and effective practice changes during the COVID-19 pandemic. Ongoing monitoring and adjustments are necessary in rapidly changing times.

Nutrition and heart failure: impact of drug therapies and management strategies.

Nutrition impairment commonly occurs in patients with heart failure and affects disease progression. Vitamin and mineral deficiencies are associated with early mortality, particularly in patients classified as cachectic. Guideline-based therapies approved for heart failure, such as loop diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, aldosterone antagonists, and beta-adrenergic blockers, can lead to electrolyte abnormalities and predispose to some vitamin and micronutrient deficits. Clinical trial evidence in support of supplementary vitamin and mineral therapies for heart failure patients is limited with the exception of documented calcium and possibly vitamin D, thiamine, and coenzyme Q10 deficiencies. This area is gaining significant attention, and research is ongoing. The clinician can help minimize morbidity from nutrition impairment through appropriate monitoring and correction of baseline and medication-induced electrolyte imbalances, in addition to vitamin and mineral supplementation when appropriate.

Ticagrelor Reduces Thromboinflammatory Markers in Patients With Pneumonia.

Despite treatment advances for sepsis and pneumonia, significant improvements in outcome have not been realized. Antiplatelet therapy may improve outcome in pneumonia and sepsis. In this study, the authors show that ticagrelor reduced leukocytes with attached platelets as well as the inflammatory biomarker interleukin (IL)-6. Pneumonia patients receiving ticagrelor required less supplemental oxygen and lung function tests trended toward improvement. Disruption of the P2Y12 receptor in a murine model protected against inflammatory response, lung permeability, and mortality. Results indicate a mechanistic link between platelets, leukocytes, and lung injury in settings of pneumonia and sepsis, and suggest possible therapeutic approaches to reduce complications.(Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor [XANTHIPPE]; NCT01883869).

Selexipag for the treatment of pulmonary arterial hypertension.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosing and administration, and place in therapy of selexipag, an orally administered selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension (PAH), are reviewed. SUMMARY: The first-in-class oral prostacyclin IP receptor agonist selexipag (Uptravi, Actelion Pharmaceuticals) was approved by the Food and Drug Administration in December 2015. Selexipag is rapidly hydrolyzed to a long-acting metabolite that binds with high selectivity to IP receptors, resulting in vasodilation, inhibition of platelet aggregation, and antiinflammatory effects. Results of a long-term, placebo-controlled, clinical outcomes-driven trial showed that selexipag significantly reduced the occurrence of the composite primary outcome (all-cause mortality and development of PAH-related complications). Selexipag is indicated for use in patients with World Health Organization functional class (FC) II or III disease. The recommended initial selexipag dosage is 200 µg twice daily. Like prostanoid analogs, selexipag has a dose-dependent adverse-effect profile that includes nausea, vomiting, diarrhea, headache, and musculoskeletal pain. Although selexipag offers distinct pharmacologic advantages over other agents for the treatment of PAH, important issues of cost and access must be considered. CONCLUSION: Selexipag is an oral prostacyclin IP receptor agonist approved for use as monotherapy or in combination with other therapies to slow PAH progression and reduce the risk of hospitalization in patients with FC II or III symptoms. Its stability and relatively long half-life offer conveniences over conventional prostanoid therapies.

Polypharmacy in Cardiovascular Medicine: Problems and Promises!

BACKGROUND: Polypharmacy is now a frequent aspect and reality of current medicine practice, driven by managing multiple comorbidities, especially in older adults. However and unfortunately, polypharmacy can expose patients to adverse drug reactions, and drug-drug or drug-disease interactions. On the other hand, clinicians are often hesitant to add new drugs to complex regimens even when recommended by evidence-based medicine and guidelines. In addition, there is frequently a failure to assess which medications might not be beneficial and may therefore be stopped. METHOD: Cardiovascular disease prevalence is increasing despite the efforts to prevent this with pandemics of obesity and diabetes as leading causes. The healthcare system is facing an increasing number of cardiovascular diseases in older patients with multiple comorbidities. New cardiovascular guidelines encourage multiple drug use to control these conditions and improve mortality and morbidity. However, use of multiple drugs can lead to inappropriate drug interactions and increased adverse outcomes. On the other hand, the so-called polypill has been proposed as a means to decrease the burden of multiple medications as well as increase cardiovascular disease prevention. CONCLUSION: This review discusses multiple issues of polypharmacy and its challenges, with a focus on cardiovascular diseases.

Chronologic Changes and Correlates of Loop Diuretic Dose in Patients with Left Ventricular Assist Device.

No study has systematically evaluated the prevalence and dosages of diuretic use for patients after left ventricular assist device (LVAD) implantation. The primary objective was to characterize chronologic change in prevalence and doses of loop diuretics after LVAD placement. The secondary objective was to identify correlates of actual doses of loop diuretics. We retrospectively reviewed medical records of adult patients with LVAD implantation at the University of Kentucky. Prevalence of diuretic use and furosemide equivalent dose were assessed before LVAD implantation and at seven time points thereafter: 1 week, 1 month, 3 months, 6 months, 1 year, 18 months, and 2 years. Correlation analyses and linear mixed modeling were used to identify correlates of diuretic dose before and after LVAD implantation. Eighty-two consecutive eligible patients were reviewed. The prevalence of loop diuretic use was 95% at baseline but significantly lower than that at all subsequent time points (p < 0.048 for all). Nevertheless, more than half of patients on whom we had such follow-up data were on loop diuretics 2 years after LVAD implantation. Average furosemide equivalent dose was significantly lower at every time point after implantation compared with baseline (p < 0.006 for all). Blood urine nitrogen (BUN) was the most robust predictor of dose after LVAD implant. The prevalence and average furosemide equivalent dose were significantly reduced after LVAD implantation, but the use of loop diuretic remained more than 50% for up to 2 years. Consistent association with BUN may indirectly indicate overuse of diuretics post-LVAD implant.

An Update on the Management of Pulmonary Arterial Hypertension and the Pharmacist's Role.

Pulmonary arterial hypertension (PAH) is a rare medical condition that significantly shortens life expectancy. The lack of understanding and complexity of treatments frequently lead to delays in diagnosis and treatment of patients. This is worsened by the gap in medical education related to the rarity of disease and the subspecialty nature of management. Advancements in diagnostics and treatment in recent years makes a review of this nature important and timely. Understanding the specialty nature of drug therapy, the complexities of managing prostacyclin analogs, and treatment algorithms are essential for pharmacists caring for these patients in both acute and ambulatory settings. This review article will provide an overview of published guidelines as well as discuss new therapies, clinical controversies, and the pharmacist's role in the management of these patients.

Obesity and Antiplatelets-Does One Size Fit All?

Antiplatelet therapy has become a cornerstone in the management of many vascular diseases. With growing antiplatelet options, attention has focused on their comparative effectiveness in specific patient populations. Perhaps one of the least defined factors influencing efficacy of these agents is body mass and obesity. Evidence from preclinical models established that obesity promotes inflammation that in turn enhances platelet reactivity. Thus, adiposity has the potential to diminish or alter the therapeutic effect of antiplatelet therapy. Pharmacodynamic analyses suggest a potential need for dose adjustments of antiplatelet therapy in obese patients. Yet, obese patients paradoxically have better outcomes after acute coronary syndromes. In this review, we identify a critical need for clinical studies with outcome data to enable the development of recommendations for optimal antiplatelet regimens in obese individuals. Until such data exists, healthcare providers should be aware of the potential impact of obesity on the efficacy of anti-platelet therapy.

Dose Related Patterns of Ventricular Arrhythmia due to Carvedilol Withdrawal in Patients with Systolic Heart Failure.

OBJECTIVES: This study evaluates the impact of carvedilol dose changes on the ventricular arrhythmia event rates for patients > 18 years of age with systolic heart failure and examines dose dependent effects of carvedilol withdrawal in dose reduction and discontinuation subgroups. METHODS: This retrospective cohort study included patients with systolic heart failure (EF < 40%) receiving carvedilol. The primary outcome was incidence of ventricular arrhythmia. Ventricular arrhythmia event rates were compared among carvedilol dose continuation, reduction and discontinuation groups. To assess dose dependent effects of beta-blocker withdrawal, dose reduction and discontinuation groups were divided into subgroups. RESULTS: Dose discontinuation (n=64) or reduction group (n=83) had significantly higher ventricular arrhythmia rates compared with dose continuation group (n=262) (65.6 vs. 33.7 vs. 15.3%, p < 0.001 for both comparisons). Dose discontinuation group also had a significantly higher ventricular arrhythmia event rate compared with dose reduction group (p<0.001). There were no significant differences in ventricular arrhythmia event rates among dose discontinuation or reduction subgroups. CONCLUSION: Continuation of carvedilol therapy was associated with a substantially lower ventricular arrhythmia event rate compared with reduction or discontinuation of carvedilol therapy. Dose dependent effects of beta-blocker withdrawal in subgroup analyses were not found.